Mitigation of Oxidative Stress Pathways in the Diabetic Cornea and Lacrimal Glands Contributes to the Rapid Reversal of Diabetic Dry Eye by Naltrexone

Purpose: To determine whether topical naltrexone (NTX) treatment can decrease the elevated reactive oxygen species pathways and select proinflammatory cytokines in the rat cornea and lacrimal glands that are elevated in diabetic dry eye. Methods: Type 1 diabetic male and female Sprague-Dawley rats were rendered hyperglycemic for 6-8 weeks and then treated topically with NTX eyedrops twice daily for 15 days. Corneal epithelium and lacrimal glands were evaluated for expression of dihydroethidium, C/EBP homologous protein, and NADPH oxidase -2 (NOX-2) as well as the proinflammatory cytokines interleukin (IL) -1β, IL-6, and tumor necrosis factor alpha (TNF-α) to identify pathways targeted in the mitigation of diabetic dry eye. Results: Type 1 diabetes resulted in dry eye and corneal surface insensitivity, accompanied by increased levels of oxidative stress and inflammation mediators in both corneal epithelium and lacrimal glands. Topical NTX treatment restored tear volume and corneal surface sensitivity, and significantly reduced expression of dihydroethidium, C/EBP homologous protein, and NOX-2, as well as proinflammatory cytokines IL-1β, IL-6, and TNF-α in male and female diabetic rats. Conclusions: Blockade of the opioid growth factor (OGF)-OGF receptor system with topical NTX rapidly reversed diabetic dry eye and restored corneal surface sensitivity. The mechanism involved downregulating oxidative stress and decreasing proinflammatory cytokines to levels at or below those of nondiabetic rats of the same sex. These findings support a mechanistic role for OGF receptor blockade in the reversal of diabetic dry eye.